Ynamide‐Mediated Peptide Bond Formation: Mechanistic Study and Synthetic Applications

Ynamides, a class of novel coupling reagents for peptide synthesis, facilitated peptide bond formation in a one‐pot, two‐step manner with α‐acyloxyenamide active esters of amino acids as stable intermediates. Ynamide‐mediated peptide synthesis proceeded by a reaction mechanism that is completely different from that of conventional coupling reagents and exhibited superiority in addressing the issue of racemization/epimerization during peptide bond formation. Herein, we present a systematic mechanistic analysis, including kinetics and Brønsted‐type structure–reactivity studies and density functional theory calculations, providing unprecedented mechanistic insight into ynamide‐mediated peptide bond formation. Based on these mechanistic studies, significant improvements were made, and the applicability of ynamide‐mediated peptide bond formation was successfully expanded to peptide fragment condensation, head‐to‐tail cyclization and solid‐phase peptide synthesis. Ynamide coupling reagents combine the advantages of conventional active esters and coupling reagents, while overcoming their disadvantages, and exhibit superiority in addressing the notorious racemization/epimerization issue. The applicability of ynamide coupling reagents has been successfully expanded to peptide fragment condensation, head‐to‐tail cyclization, and solid‐phase peptide synthesis on the basis of a systematic mechanistic study.